Product comprising a transduction inhibitor of heterotrimeric G protein signals combined with another anti-cancer agent for therapeutic use in the treatment of cancer

ABSTRACT

A composition for treating cancer comprising an anti-tumorally effective amount of a product comprising at least one transduction inhibitor of heterotrimeric G protein signals and at least one other anti-cancer agent selected from the group consisting of prenyltransferase inhibitors, taxol and its analogues, gemcitabine and camptothecin and its analogues, administered simultaneously, separately or spread over a period of time and a pharmaceutical carrier.

The present invention relates to a product comprising at least onetransduction inhibitor of heterotrimeric G protein signals, thatpreferably corresponds to general formula (I) defined below, combinedwith at least one other anti-cancer agent, preferably chosen from thegroup comprising taxol, taxol analogues, gemcitabine andprenyltransferase inhibitors, particularly the compounds of generalformulae (II) or (III) defined below, for therapeutic use,simultaneously, separately or spread over a period of time, in thetreatment of cancer.

The development of new anti-cancer treatments occurs largely by thediscovery of effective combinations between different therapeuticclasses to accentuate the antitumorous effect of each class.

The combination of the anti-Her-2/neu antibody and cisplatin oretoposide inhibits the proliferation of mammary tumor cells in a moresignificant manner than the simple addition of the effects of eachproduct (cf. Pegram, M., et al., Oncogene, 18(1999): 2241-2251). Thecombination ofrthis antibody with taxol or methotrexate shows anaddition of the effects whilst its combination with 5-fluorouracyl showsan antagonism of the products (McGuire W. P. et al., Semin. Oncol. 1997Feb. 24 (1 Suppl 2):S2-13-S2-16).

The farnesyltransferase inhibitors act in synergy with agents whichdepolymerise microtubules (taxol, epothilones) (cf. Moasser et al.,Proc. Natl. Acad. Sci. U.S.A. (1998), 95, 1369-1374). The combination offarnesyltransferase inhibitors with cytotoxic doxorubicin, cisplatin or5-fluorouracyl shows only an addition of the effects.

The heterotrimeric G proteins are, in fact, the structural associationof three distinct sub-units called α, β and γ, but function asdissociable entities constituted by sub-units α on the one hand and β/γdimers on the other. Different forms of sub-units of α, β and γ type aredescribed.

The G proteins participate in the transmission of signals outside thecell, thanks to its interaction with receptors with seven transmembranedomains, inside using different effectors including adenylate cyclase,phospholipase C or also the ionic channels. The adenylate cyclase enzymegenerates cyclic adenosine monophosphate (cAMP) (cf. Gilman, Biosci.Rep. (1995), 15, 65-97). Thus it is known, that in order to activateadenylate cyclase, it is necessary form the G proteins to betransitionally in a heterotrimeric form, in which form the monomerconstituted by an a: sub-unit is associated with the dimer constitutedby the β and γ sub-units. It is also known that for the G proteins to befound in their heterotrimeric form, they must be fixed by their γsub-units to the membrane. It is only in this situation that the signaloutside the cell can activate the α sub-unit of a G protein, which can,after disassociation, modulate the effectors such as adenylate cyclaseand modulate the production of cAMP.

It is also known that the β/γ dimers can directly activate the effectorsleading to the activation of kinases regulated by extracellular signals(ERKs) or MAP kinases. A direct link between the β/γ sub-units and thesrc or src-like kinases has been demonstrated (cf. Gutkind, J. Biol.Chem. (1998), 273, 1839-1842).

The harmful effects of an abnormal cAMP level are also known and occurin particular at the level of the following biological functions ordisorders: smell, taste, light perception, neurotransmission,neurodegeneration, endocrine and exocrine gland functions, autocrine andparacrine regulation, arterial tension, embryogenesis, benign cellproliferation, oncogenesis, viral infection and immunological functions,diabetes and obesity.

The Applicant has itself already described in PCT Patent Application WO00/02881 the use of the compounds of general formula (I) as definedhereafter as G protein inhibitors. Certain products had been describedpreviously in the PCT Patent Application WO 97/30053.

Prenyltransferase inhibitors are already used in the field of cancertreatment (cf. Sebti et al., Pharmacol. Ther. (1997), 74, 103-114;Sepp-Lorenzino et al., Cancer Res. (1997), 55, 5302-5309). Theusefulness of prenyltransferase inhibitors in this type of treatmentcomes from their action which prevents prenylation at the level of theRas substrate. However, the prenylation of certain forms of Ras is notmodified by the prenylation inhibitors (Lerner et al., Oncogene (1997),15, 1283-1288).

As far as the anti-cancer agents are concerned, prenyltransferaseinhibitors are in particular described in the following PatentApplications: PCT Applications WO 97/21701, WO 97/16443, WO 98/00409, WO96/21456, WO 97/24378, WO 97/17321, WO 97/18813, WO 95/00497; U.S. Pat.No. 5,532,359, U.S. Pat. No. 5,523,430, U.S. Pat. No. 5,510,510 and U.S.Pat. No. 5,627,202. Moreover, the compounds of general formula (II) havebeen described in PCT Patent Application WO 00/39130. Taxol is inparticular described in Merck Index, 11th ed., 1989, under headingnumber 9049 and in the references cited. Camptothecin analogues have inparticular been described in the U.S. Pat. No. 4,894,456 and in the PCTPatent Applications WO 94/11376, WO 97/00876, WO 98/28304, WO 98/28305,WO 99/11646 and WO 99/33829.

A product according to the invention offers the advantage of being ableto use lower doses of the anti-cancer agents chosen, which has the maineffect of reducing the toxicity of the treatment whilst obtaining apharmacological effect with a minimum of additive.

A subject of the invention is therefore a product comprising at leastone transduction inhibitor of heterotrimeric G protein signals combinedwith at least one anti-cancer agent, preferably chosen from the groupcomprising taxol, taxol analogues, gemcitabine and prenyltransferaseinhibitors, for therapeutic use simultaneously, separately or spreadover a period of time, in the treatment of cancer.

Preferably, the prenyltransferase inhibitor combined with thetransduction inhibitor of heterotrimeric G protein signals is afarnesyltransferase inhibitor.

Although taxol, taxol analogues, gemcitabine and prenyltransferaseinhibitors are preferred, a number of other anti-cancer agents can bealso combined, according to the invention, with a transduction inhibitorof heterotrimeric G protein signals, for example: enzyme inhibitors suchas topoisomerase inhibitors such as camptothecin and camptothecinanalogues (in the form of analogues comprising an E lactonic ring withsix members such as for example the compounds described in PCT PatentApplication WO 94/11376, in the form of analogues comprising an Elactonic ring with seven members such as for example the compoundsdescribed in PCT Patent Application WO 97/00876 or also in the form ofopen tetracyclic analogues such as for example the compounds describedin the PCT Patent Application WO 99/33829), Cdc25 phosphataseinhibitors, MAP kinase or MAP kinase kinase inhibitors, protein kinase Cinhibitors, tyrosine kinase inhibitors, telomerase inhibitors; inductorsof apoptosis; alkylating agents such as cisplatin; anti-metabolic agentssuch as 5-fluorouracil; differentiation agents; cell spindle poisons;angiogenesis inhibitors; anti-hormones or antagonists of the steroidreceptors; antioxidants; antisense agents; anti-p53 agents (genetherapy); chemo-prevention agents; anti-viral agents; immuno-therapeuticagents; antibodies such as heregulin.

Preferably, the transduction inhibitor of heterotrimeric G proteinsignals is a compound of general formula (I)

corresponding to sub-formulae (I_(A)) or (I_(B)):

in which:

X represents R₁₂ and Y represents R₈, or X and Y complete a ring with 6members, the X—Y mixture representing the —CH(R₈)—CH(R₉)— radical;

R₁ represents H, an alkyl or alkylthio radical;

R₂ and R₃ independently represent H or an alkyl radical;

R₄ represents H₂ or O;

R₅ represents H, or one of the alkyl, alkenyl, alkynyl, aryl, aralkyl,heterocyclyl or heterocyclylalkyl radicals, these radicals being able tobe optionally substituted by radicals chosen from the group comprisingan alkyl radical, —O—R₁₀, —S(O)_(m)R₁₀ (m representing 0, 1, or 2),—N(R₁₀)(R₁₁), —N—C(O)—R₁₀, —NH—(SO₂)—R₁₀, —CO₂—R₁₀, C(O)—N(R₁₀)(₁₁), and—(SO₂)—N(R₁₀)(R₁₁);

R₆ and R₇ independently represent H, a —C(O)—NH—CHR₁₃—CO₂R₁₄ radical, orone of the alkyl, aryl, aralkyl, heterocyclyl or heterocyclylalkylradicals, these radicals being optionally substituted by radicals chosenfrom the group comprising OH, alkyl or alkoxy, N(R₁₀)(R₁₁), COOH,CON(R₁₀)(R₁₁), and halo radicals,

or R₆ and R₇ together form an aryl radical or a heterocycle;

R₈ and R₉ independently represent H or one of the alkyl, aryl, aralkyl,heterocyclyl or heterocyclylalkyl radicals, these radicals being able tobe optionally substituted by radicals chosen from the group comprisingOH, alkyl or alkoxy, N(R₁₀)(R₁₁), COOH, CON(R₁₀)(R₁₁) and halo radicals,

or R₈ and R₉ together form an aryl radical or a heterocycle;

R₁₀ and R₁₁, independently represent H, an aryl or heterocyclyl, or analkyl, aralkyl or heterocyclylalkyl radical;

R₁₂ represents NR₉, S, or O;

R₁₃ represents an alkyl radical optionally substituted by a radicalchosen from the alkyl, —OR₁₀, —S(O)_(m)R₁₀ (m representing 0, 1, or 2)and —N(R₁₀)(R₁₁) radicals;

R₁₄ represents H or an alkyl radical;

or a pharmaceutically acceptable salt of such a compound.

By lower alkyl radical, is meant a linear or branched alkyl radicalcontaining 1 to 6 carbon atoms, and in particular the methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, pentyl,neopentyl, isopentyl, hexyl, isohexyl radicals. By heterocycle radical,is meant a radical constituted by one or more rings and including atleast one heteroatom. By lower arylalkyl, heterocycle alkyl, alkylthioor alkoxy radical, is meant the radicals of which the alkyl radical hasthe meaning as indicated previously.

Preferably, the compounds of general formula (I) are such that:

X and Y complete a ring with 6 members, the X—Y combination representingthe —CH(R₈)—CH(R₉)— radical;

R₁ represents an alkyl radical or lower;

R₂ and R₃ represent H;

R₄ represents O;

R₅ represents H, or one of the lower alkyl, cycloalkyl, cycloalkylalkyl,lower arylsulphonylalkyl, lower aralkoxyalkyl radicals, these radicalsbeing able to be optionally substituted by radicals chosen from thegroup comprising a lower alkyl or —O—R₁₀ radical;

R₆ and R₇ independently represent H or an aryl radical optionallysubstituted by radicals chosen from the group comprising the OH, alkylor lower alkoxy radicals,

R₈ and R₉ represent H;

and R₁₀ and R₁₁, independently represent H or a lower alkyl radical.

The following compounds of general formula (1) are in particularpreferred for the invention:

-   7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-(2-methylphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;-   7-(2-amino-1-oxo-3-thiopropyl)-8-butyl-2-(2-methoxyphenyl)-5,6,7,8-tetrahydro-imidazo[1,2a]pyrazine;-   bis-1,1′-[7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(1-methylpropyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine]disulphide;-   bis-1,1′-7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-(2-methoxy-phenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine    disulphide;-   bis-1,1′-7-(2-amino-1-oxo-3-thiopropyl-(2-(1-naphthyl)-8-(2-methylpropyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazin-7-yl)    disulphide;-   7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-phenyl-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;-   7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(phenylmethoxy)methyl-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;-   7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(1-phenylmethoxy)ethyl-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;-   7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(phenoxyethyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;-   7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(phenoxyethyl)-5,6,7,8-tetrahydro-imidazo[1,2a]pyrazine,    or its dimeric form;-   and    7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(phenylsulphonylethyl)    -5,6,7,8-tetrahydro-imidazo[1,2a]pyrazine;    or a pharmaceutically acceptable salt of one of the latter.

Preferably, when the anti-cancer agent combined with a transductioninhibitor of heterotrimeric G protein signals is a prenyltransferaseinhibitor, it is a farnesyltransferase inhibitor.

More preferentially, the farnesyltransferase inhibitor is chosen fromthe group composed:

-   -   of a compound of general formula (II)        in which:

n1 represents 0 or 1;

X represents, independently, each time that it occurs,(CHR¹¹)_(n3)(CH₂)_(n4)Z(CH₂)_(n5);

Z representing O, N(R¹²), S, or a bond;

n3 representing, independently, each time that it occurs, 0 or 1;

each of n4 and n5 representing, independently, each time that theyoccur, 0, 1, 2, or 3;

Y represents, independently, each time that it occurs, CO, CH₂, CS, or abond;

R¹ represents one of the

or N(R²⁴R²⁵) radicals;

each of R², R¹¹, and R¹² representing, independently, each time that itoccurs, H or an optionally substituted radical chosen from the groupconsisting of a (C₁₋₆)alkyl radical and an aryl radical, said optionallysubstituted radical being optionally substituted by at least one radicalchosen from the R⁸ and R³⁰ radicals, each substituent being chosenindependently of the others;

R³ represents, independently, each time that it occurs, H or anoptionally substituted radical chosen from the group consisting of the(C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₂₋₆)alkynyl, (C₃₋₆)cycloalkyl,(C₃₋₆)cycloalkyl(C₁₋₆)alkyl, (C₅₋₇)cycloalkenyl,(C₅₋₇)cycloalkenyl(C₁₋₆)alkyl, aryl, aryl(C₁₋₆)alkyl, heterocyclyl, andheterocyclyl(C₁₋₆)alkyl radicals, said optionally substituted radicalbeing optionally substituted by at least one radical chosen from the R³⁰radicals, each substituent being chosen independently of the others;

each of R⁴ and R⁵ represents, independently, each time that it occurs, Hor an optionally substituted radical chosen from the group consisting ofthe (C₁₋₆)alkyl, (C₃₋₆)cycloalkyl, aryl and heterocyclyl radicals, saidoptionally substituted radical being optionally substituted by at leastone radical chosen from the R³⁰ radicals, each substituent being chosenindependently of the others, or R⁴ and R⁵ taken together with the carbonatoms to which they are attached together form an aryl radical;

R⁶ represents, independently, each time that it occurs, H or anoptionally substituted radical chosen from the group consisting of the(C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₃₋₆)cycloalkyl,(C₃₋₆)cycloalkyl(C₁₋₆)alkyl, (C₅₋₇)cycloalkenyl,(C₅₋₇)cycloalkenyl(C₁₋₆)alkyl, aryl, aryl(C₁₋₆)alkyl, heterocyclyl andheterocyclyl(C₁₋₆)alkyl radicals, said optionally substituted radicalbeing optionally substituted by at least one radical chosen from the OH,(C₁₋₆)alkyl, (C₁₋₆)alkoxy, —N(R⁸R⁹), —COOH, —CON(R⁸R⁹) and haloradicals, each substituent being chosen independently of the others;

Each time that it occurs, R⁷ represents, independently, H, ═O, ═S, H oran optionally substituted radical chosen from the group consisting ofthe (C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₃₋₆)cycloalkyl,(C₃₋₆)cycloalkyl(C₁₋₆)alkyl, (C₅₋₇)cycloalkenyl,(C₅₋₇)cycloalkenyl(C₁₋₆)alkyl, aryl, aryl(C₁₋₆)alkyl, heterocyclyl andheterocyclyl(C₁₋₆)alkyl radicals, said optionally substituted radicalbeing optionally substituted by at least one radical chosen from the OH,(C₁₋₆)alkyl, (C₁₋₆)alkoxy, —N(R⁸R⁹), —COOH, —CON(R⁸R⁹) and haloradicals, each substituent being chosen independently of the others;

each of R⁸ and R⁹ representing, independently, each time that it occurs,H, (C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₂₋₆)alkynyl, aryl, or aryl(C₁₋₆)alkyl;

R¹⁰ represents C;

or, when n1=0, R⁶ and R⁷ can be taken together with the carbon atoms towhich they are attached to form an aryl or cyclohexyl radical;

R²¹ represents, independently, each time that it occurs, H or anoptionally substituted radical chosen from the group consisting of the(C₁₋₆)alkyl and aryl(C₁₋₆)alkyl radicals, said optionally substitutedradical being optionally substituted by at least one radical chosen fromthe R⁸ and R³⁰ radicals, each substituent being chosen independently ofthe others;

R²² represents H, (C₁₋₆)alkylthio, (C₃₋₆)cycloalkylthio, R⁸—CO—, or asubstituent of formula

each of R²⁴ and R²⁵ represents, independently, each time that it occurs,H, (C₁₋₆)alkyl or aryl(C₁₋₆)alkyl;

R³⁰ represents, independently, each time that it occurs, (C₁₋₆)alkyl,—O—R⁸, —S(O)_(n6)R⁸, —S(O)_(n7)N(R⁸R⁹), —N(R⁸R⁹), —CN, —NO₂, —CO₂R⁸,—CON(R⁸R⁹), —NCO—R⁸, or halogen, each of n6 and n7 representing,independently, each time that it occurs, 0, 1 or 2;

said heterocyclyl radical being azepinyl, benzimidazolyl,benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl,benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl,cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl,dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulphone, furyl,imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl,isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl,isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl,oxadiazolyl, 2-oxoazepinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxopyrrolidinyl, piperidyl, piperazinyl, pyridyl, pyridyl-N-oxide,quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolinyl,tetrahydro-quinolinyl, thiamorpholinyl, thiamorpholinyl sulphoxide,thiazolyl, thiazolinyl, thienofuryl, thienothienyl or thienyl;

said aryl radical being phenyl or naphthyl;

it being understood that:when n1=1, R¹⁰ is C and R⁶ represents H, then R¹⁰ and R⁷ can, takentogether, form the

or when n1=1, R¹⁰ is C, and R⁷ is ═O, —H, or ═S, then R¹⁰ and R⁶ can,taken together, form the

with each of X¹, X², and X³ representing, independently, H, a halogenatom, —NO₂, —NCO—R⁸, —CO₂R⁸, —CN, or —CON(R⁸R⁹); andwhen R¹ is N(R²⁴R²⁵), then n3 represents 1, each of n4 and n5 represents0, Z is a bond, and R³ and R¹¹ can, taken together, form the

with n2 representing an integer from 1 to 6, and each of X⁴ and X⁵representing, independently, H, (C₁₋₆)alkyl or aryl, or X⁴ and X⁵ takentogether, forming a (C₃₋₆)cycloalkyl radical;

-   -   of a compound of general formula (III)        in which:

R¹ represents H or an alkyl, OR¹⁰, SR¹⁰ or NR¹¹R¹² radical;

R² represents H or an alkyl radical;

R³, R⁴ and R⁵ represent, independently, H, a halogen atom or an alkyl,trihalomethyl, hydroxy, cyano or alkoxy radical;

R⁶ represents H or an alkyl radical;

R⁷ represents H, a halogen atom or an alkyl, hydroxyalkyl, amino,hydroxycarbonyl radical;

R⁸ and R⁹ represent, independently, H, a halogen atom or a cyano, alkyl,trihalomethyl, alkoxy, alkylthio or dialkylamino radical;

R¹⁰ represents H or an alkyl or alkylcarbonyl radical;

R¹¹ represents H or an alkyl radical;

R¹² represents H or an alkyl or alkylcarbonyl radical;

and Y represents O or S;

-   -   and a pharmaceutically acceptable salt of a compound of general        formula (II) or of a compound of general formula (III).

In certain cases, compounds which are of use in the composition of aproduct according to the present invention can comprise asymmetricalcarbon atoms. As a result, said compounds have two possible enantiomericforms, i.e. the “R” and “S” configurations. The present inventionincludes the two enantiomeric forms and all combinations of these forms,including the racemic mixtures “RS”. In an effort to simplify matters,when no specific configuration is as indicated in the structuralformulae, it should be understood that both enantiomeric forms and theirmixtures are represented.

By alkyl, unless specified otherwise, is meant a linear or branchedalkyl radical containing 1 to 6 carbon atoms. By alkylcarbonyl,alkylthio, alkoxy, alkylamino, dialkylamino, alkenyl, alkynyl, aralkyl,heterocyclylalkyl radicals, is meant respectively the alkylcarbonyl,alkylthio, alkoxy, alkylamino, dialkylamino, alkenyl, alkynyl, aralkyl,heterocyclylalkyl radicals of which the alkyl radical has the meaningindicated previously.

By linear or branched alkyl having 1 to 6 carbon atoms, is meant inparticular the methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl and tert-butyl, pentyl, neopentyl, isopentyl, hexyl, isohexylradicals. Finally, by halogen, is meant the fluorine, chlorine, bromineor iodine atoms.

When a chemical structure such as used here has an arrow emanating fromit, the arrow indicates the attachment point. For example, the structure

is a pentyl radical. When a value in brackets appears close to thearrow, the value indicates where the attachment point can be found inthe compound. For example, in general formula (II)

as defined previously, when R¹⁰ and R⁷ are taken together to form the

the following structure results:

Finally, by pharmaceutically acceptable salt, is meant in particular theaddition salts of inorganic acids such as hydrochloride, hydrobromide,hydroiodide, sulphate, phosphate, diphosphate and nitrate or organicacids such as acetate, maleate, fumarate, tartrate, succinate, citrate,lactate, methanesulphonate, p-toluenesulphonate, pamoate and stearate.The salts formed from bases such as sodium or potassium hydroxide alsofall within the scope of the present invention, when they can be used.For other examples of pharmaceutically acceptable salts, reference canbe made to “Salt selection for basic drugs”, Int. J. Pharm. (1986), 33,201-217.

In particular, transduction inhibitors of heterotrimeric G proteinsignals could, according to the invention, be usefully combined with thefollowing compounds:

Prenyltransferase inhibitors, and in particular farnesyltransferaseinhibitors such as1-(2-(1-((4-cyano)phenylmethyl)imidazol-4-yl)-1-oxoethyl-2,5-dihydro-4-(2-methoxy-phenyl)imidazo[1,2c][1,4]benzodiazepine,4-(2-bromophenyl)-1-(2-(1-((4-cyano-3-methoxy)phenylmethyl)-imidazo-5-yl)-1-oxoethyl)-1,2-dihydro-8-fluoro-imidazo[1,2a][1,4]-benzodiazepineor(±)-4-(3-chlorophenyl)-6-[(4-chlorophenyl)-amino-(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)quinolinone;

cell spindle poisons such as taxol;

alkylating agents such as cisplatin;

anti-metabolic agents such as gemcitabine or 5-fluorouracyl.

Preferably, the transduction inhibitors of heterotrimeric G proteinsignals used in the invention are such that they correspond to generalsub-formula (IA) as defined previously in which:

R₁ represents H;

R₂ and R₃ represent, independently, H or a lower alkyl radical;

R₄ represents O;

R₅ represents H, or one of the lower alkyl, cycloalkyl orcycloalkylalkyl radicals;

R₆ represents an aryl radical optionally substituted by radicals chosenfrom the group comprising the OH, alkyl or lower alkoxy, N(R₁₀)(R₁₁),COOH, CON(R₁₀)(R₁₁) and halo radicals;

R₁₀ and R₁₁, representing independently H or a lower alkyl radical;

or are salts of these same compounds.

Preferably, when they are used for the invention, the compounds ofgeneral formula (II) are those in which are found, independently, theradicals presenting the following characteristics:

R¹ representing the

R²¹ representing an aralkyl radical the aryl group of which can beoptionally substituted by a radical or radicals chosen from a halogenatom and the cyano, hydroxy, alkoxy, amino, alkylamino and dialkylaminoradicals;

R⁴ representing an aryl radical optionally substituted by a radical orradicals chosen from a halogen atom and the hydroxy, alkoxy, amino,alkylamino and dialkylamino radicals;

X representing an alkylene radical containing 1 to 6 carbon atoms;

Y representing CO;

n1=1, R¹⁰ being C, R⁶ representing H and R¹⁰ and R⁷ taken together,forming the

each of X¹, X², and X³ representing, independently, H or a halogen atom.

Preferably, when they are used for the invention, the compounds ofgeneral formula (III) are those in which are found, independently, theradicals presenting the following characteristics:

-   -   R¹ representing OH or NH₂;    -   R² representing alkyl and preferably methyl;    -   one of R³, R⁴ and R⁵ representing a halogen atom;    -   R⁶ representing alkyl and preferably methyl;    -   one of R⁸ and R⁹ representing a halogen atom;    -   Y representing O.

According to a particularly preferred variant of the invention, thetransduction inhibitors of heterotrimeric G protein signals are chosenfrom the group composed of:

-   -7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-(2-methylphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;    and-   -7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-phenyl-5,6,7,8-tetrahydro-imidazo[1,2a]pyrazine;    and pharmaceutically acceptable salts of the latter.

Still according to a particularly preferred variant of the invention,the anti-cancer agents combined with said transduction inhibitors ofheterotrimeric G protein signals are chosen from the group composed of:

-   1-(2-(1-((4-cyano)phenylmethyl)imidazol-4-yl)-1-oxoethyl-2,5-dihydro-4-(2-methoxyphenyl)imidazo[1,2c][1,4]benzodiazepine;-   4-(2-bromophenyl)-1-(2-(1-((4-cyano-3-methoxy)phenylmethyl)-imidazo-5-yl)-1-oxoethyl)-1,2-dihydro-8-fluoro-imidazo[1,2a][1,4]-benzodiazepine;-   (±)-4-(3-chlorophenyl)-6-[(4-chlorophenyl)-amino-(1-methyl-1H-imidazol-5-yl)    methyl]-1-methyl-2(1H)quinolinone;-   taxol;-   gemcitabine;    and of the pharmaceutically acceptable salts of the latter.

Optionally, an additional anti-cancer compound can also be used,different from the anti-cancer agent combined with the transductioninhibitor of heterotrimeric G protein signals, in the composition of theproduct of the invention. Preferably, said additional compound is chosenfrom the group composed:

-   1-(2-(1-((4-cyano)phenylmethyl)imidazol-4-yl)-1-oxoethyl-2,5-dihydro-4-(2-methoxyphenyl)imidazo[1,2c][1,4]benzodiazepine;-   4-(2-bromophenyl)-1-(2-(1-((4-cyano-3-methoxy)phenylmethyl)-imidazo-5-yl)-1-oxoethyl)-1,2-dihydro-8-fluoro-imidazo[1,2a][1,4]-benzodiazepine-   (±)-4-(3-chlorophenyl)-6-[(4-chlorophenyl)-amino-(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)quinolinone;-   taxol;-   gemcitabine;    and pharmaceutically acceptable salts of the latter.

A subject of the invention is also a pharmaceutical compositioncomprising at least one of the products according to the invention.

The pharmaceutical compositions comprising a product according to theinvention can be in the form of a solid, for example powders, granules,tablets, gelatin capsules, liposomes or suppositories. The appropriatesolid supports can be, for example, calcium phosphate, magnesiumstearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose,methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidineand wax.

The pharmaceutical compositions comprising a product according to theinvention can also be presented in liquid form, for example, solutions,emulsions, suspensions or syrups. The appropriate liquid supports can,for example, be water, organic solvents such as glycerol or glycols, andsimilarly their mixtures, in varying proportions, in water.

The administration of a medicament according to the invention can bedone by topical, oral, parenteral route, by injection (intramuscular,sub-cutaneous, intravenous, etc.), etc. The administration route willdepend of course on the type of disease to be treated.

The following administration doses (daily, except for contra-indication)could be envisaged for the different compounds used in the compositionof a product according to the invention:

compound of general formula (I): from 50 to 200 mg/m² by intraperitonealroute;

compound of general formula (II): from 50 to 500 mg/m² per os;

taxol: 1 to 10 mg/kg (intraperitoneal route) or 1 to 3 mg/kg(intravenous route);

cisplatin: 50 to 80 mg/m²;

5-fluorouracil: 400 to 800 mg/rn² by intravenous route, theadministrations being repeated from 1 to 4 times per month;

gemcitabine: 100 to 500 mg/m² by intravenous route (perfusions lastingapproximately 6 hours).

Preparation of Certain Compounds Used in the Composition of the Productsof the Invention:

I) The compounds of general formula (I) are prepared according tomethods similar to those described in PCT Patent Application WO97/30053.

However, the following compounds have been described previously inPatent Application WO 00/02881:

-   7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-(2-methylphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;    and-   7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-phenyl-5,6,7,8-tetrahydro-imidazo[1,2a]pyrazine.

II) The compounds of general formula (II), of which1-(2-(1-((4-cyano)phenylmethyl)imidazol-4-yl)-1-oxoethyl-2,5-dihydro-4-(2-methoxyphenyl)imidazo[1,2c][1,4]benzodiazepine and4-(2-bromophenyl)-1-(2-(1-((4-cyano-3-methoxy)phenylmethyl)imidazo-5-yl)-1-oxoethyl)-1,2-dihydro-8-fluoroimidazol[1,2a][1,4]-benzodiazepine, are prepared according to the proceduresdescribed in PCT Patent Application WO 00/39130.

C) The compounds of general formula (III) are prepared according to themethods described in PCT Patent Application WO 97/21701.

Unless they are defined differently, all the technical and scientificterms used here have the same meaning as that usually understood by anordinary specialist in the field to which this invention belongs.Similarly, all the publications, patent applications, all the patentsand all other references mentioned here are incorporated by way ofreference.

The following examples are presented in order to illustrate the aboveprocedures and should in no event be considered as a limit to the scopeof the invention.

EXAMPLES

In order to illustrate the usefulness of the invention, the effect of atreatment on a tumor line of Mia-Paca2 pancreatic human cells with7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-(2-methylphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazineor7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-phenyl-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine(described in PCT Application WO 00/02881) combined with differentanti-cancer agents will be studied.

By convention, the products inhibiting the transduction ofheterotrimeric G protein signals used in the tests are identified by theletter A, and the other anti-cancer agents used in the tests by theletter B.

1) Procedures

Material

The following compounds (prepared according to the methods describedpreviously) are of use in the composition of the products tested:

-   7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-(2-methylphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine    (compound A₁);-   7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-phenyl-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine    (compound A₂);-   1-(2-(1-((4-cyano)phenylmethyl)imidazol-4-yl)-1-oxoethyl-2,5-dihydro-4-(2-methoxyphenyl)imidazo[1,2c][1,4]benzodiazepine    (compound B₁);-   taxol (compound B₂);-   gemcitabine (compound B₃);-   (±)-4-(3-chlorophenyl)-6-[(4-chlorophenyl)-amino-(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)quinolinone    (compound B₄);-   4-(2-bromophenyl)-1-(2-(1-((4-cyano-3-methoxy)phenylmethyl)-imidazo-5-yl)-1-oxoethyl)-1,2-dihydro-8-fluoro-imidazo[1,2a][1,4]-benzodiazepine    (compound B₅).    Cell Line

The cell line Mia-Paca2 (human pancreatic cancer cells) was acquiredfrom the American Tissue Culture Collection (Rockville, Md., USA).

Measurement of Cell Proliferation In Vitro

The Mia-Paca2 cells (1500 cells/wells) are cultured in 96-well platespre-coated with polyhema (Sigma) which allows only the growth of cellspresenting a tumorigenic phenotype.

On day 0, these cells are seeded in 90 μl of Dulbecco's modified Eaglemedium (Gibco-Brl, Cergy-Pontoise, France) completed with 10% of foetalcalf serum inactivated by heating (Gibco-Brl, Cergy-Pontoise, France),50000 units/l of penicillin and 50 mg/l streptomycin (Gibco-Brl,Cergy-Pontoise, France), and 2 mM of glutamin (Gibco-Brl,Cergy-Pontoise, France).

The cells were treated with increasing concentrations of two productsalone or combined in a matrix, i.e.: on day 1, with the first productfor 96 hours and on day 2 with the second product for 72 hours.According to method (t, the transduction inhibitor of heterotrimeric Gprotein signals with which the anti-cancer agent is combined isadministered before the latter, then according to method A, it is doneso after.

At the end of this period, quantification of cell proliferation isevaluated by a colorimetric test based on the cleavage of thetetrazolium salt WST1 by mitochondrial dehydrogenases in the livingcells leading to the formation of formazan (Boehringer Mannheim, Meylan,France). These tests are carried out in duplicate with 4 measurementsfor each single product and for each combination tested. This allows thenumber of living cells at the end of each treatment to be determined,i.e. the observed value. The calculated value of the living cells foreach treatment corresponds to the multiplication of the observed valuesof the effects of separate products. These observed and calculatedvalues are compared for each combination. When the observed value ofliving cells is lower than the calculated value of the living cells, asynergy is considered to exist. When the observed value is equal to thecalculated value, a additive effect is considered to exist. When theobserved value is greater than the calculated value, an antagonism isconsidered to exist.

2) Results:

The results obtained are given in the tables shown below.

The results given in Tables I, II, III, IV and IV show that the productscomprising compound A₁ combined with compound B₁, compound B₂ orcompound B₃ or those comprising compound A₂ combined with compound B₄ orcompound B₅ are capable of inhibiting the proliferation in vitro ofMia-Paca2 human tumor cells. The combined effect of the combination,evaluated by the method described in Cote, S. and Momparler, R. L.,Anticancer Drugs (1993), 4, 327-333, allows a synergy in combinationsA₁+B₁, A₁+B₂, A₁+B₃, A₂+B₄ and A₂+B₅ to be noted. TABLE I Observedvalues (method α − n = 4) Calculated values Compound A₁ Compound A₁Doses of Compound B₁ (20 μM) + (20 μM) + compound B₁ alone compound B₁compound B₁ 0 μM 100 51 ± 8.9 0.04 μM 94 ± 2.3 39 ± 8.4 47 ± 7.1 0.2 μM80 ± 4.2 23 ± 5.9 38 ± 4.9 1 μM 68 ± 2.3 23 ± 6.5 34 ± 5.0

TABLE II Observed values (method α − n = 3) Calculated values CompoundA₁ Compound A₁ Doses of Compound B₂ (20 μM) + (20 μM) + compound B₂alone compound B₂ compound B₂ 0 nM 100 49 ± 7.7 0.8 nM 100 ± 5.8 34 ±2.4 48 ± 6.7 4 nM 100 ± 0.3 32 ± 2.2 49 ± 7.5 20 nM  60 ± 10.6 17 ± 4.530 ± 7.2

TABLE III Observed values (method α − n = 3) Calculated values CompoundA₁ Compound A₁ Doses of Compound B₃ (20 μM) + (20 μM) + compound B₃alone compound B₃ compound B₃ 0 nM 100 65 ± 7.3 4 nM 95 ± 9.8 48 ± 2.159 ± 1.3 20 nM  72 ± 11.5 27 ± 6.8 45 ± 4.0 100 nM 62 ± 1.9 30 ± 4.0 40± 3.1

TABLE IV Observed values (method β − n = 2) Calculated values CompoundA₂ Compound A₂ Doses of Compound B₄ (20 μM) + (20 μM) + compound B₄alone compound B₄ compound B₄ 0 nM 100  42 ± 11.0 40 nM 104 ± 2.0  28 ±3.0  44 ± 12.0 0.2 μM 90 ± 9.0 13 ± 2.0 37 ± 6.0 1 μM 72 ± 3   14 ± 1.030 ± 7.0

TABLE V Observed values (method β − n = 3) Calculated values Compound A₂Compound A₂ Doses of Compound B₅ (20 μM) + (20 μM) + compound B₅ alonecompound B₅ compound B₅ 0 μM 100 44 ± 6.4 0.2 μM 86 ± 0.9 17 ± 2.7 38 ±5.2 1 μM 63 ± 2.6 11 ± 1.4 27 ± 3.0

1. A composition for treating cancer comprising an anti-tumorallyeffective amount of a product comprising at least one transductioninhibitor of heterotrimeric G protein signals and at least one otheranti-cancer agent selected from the group consisting ofprenyltransferase inhibitors, taxol and its analogues, gemcitabine andcamptothecin and its analogues, administered simultaneously, separatelyor spread over a period of time and a pharmaceutical carrier.
 2. Thecomposition of claim 1 wherein the other anti-cancer agent is aprenyltransferase inhibitor.
 3. The composition of claim 2 wherein theprenyltransferase inhibitor is a farnesyltransferase inhibitor.
 4. Thecomposition of claim 1 comprising at least one transduction inhibitor ofheterotrimeric G protein signals of the formula

corresponding to the sub-formulae

wherein X is R₁₂ and Y is R₈, or X and Y together complete a ring with 6members, the X—Y mnixture is —CH(R₈)—CH(R₉)— radical; R₁ is selectedfrom the group consisting of H, alkyl and alkylthio; R₂ and R₃ areindividually H or alkyl; R₄ is H₂ or O; R₅ is selected from the groupconsisting of H, alkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclyland heterocyclylalkyl unsubstituted or substituted by a member selectedfrom the group consisting of alkyl, —O—R₁₀—S(O)_(m)R₁₀ (m is 0, 1, or2), —N(R₁₀)R(₁₁), —N—C(O)—R₁₀, —NH—(SO₂)—R₁₀, —CO₂—R₁₀, C(O)—N(R₁₀)(R₁₁), and —(SO₂)—N(R₁₀) (R₁₁); R₆ and R₇ are individually selected fromthe group consisting of H, —C(O)—NH—CHR₁₃—CO₂R₁₄, alkyl, aryl, aralkyl,heterocyclyl and heterocyclylalkyl, the latter four unsubstituted orsubstituted by a member selected from the group consisting of OH, alkyl,alkoxy, —N(R₁₀)(R₁₁), —COOH, —CON(R₁₁) (R₁₁), and halo, or R₆ and R₇together form aryl or heterocycle; R₈ and R₉ are individually selectedfrom the group consisting of H, alkyl, aryl, aralkyl, heterocyclyl andheterocyclylalkyl unsubstituted or substituted by a member of the groupconsisting of —OH, alkyl, alkoxy —N(R₁₀)(R₁₁), —COOH, —CONR(₁₀)(R₁₁) andhalo; or R₈ and R₉ together form aryl or heterocycle; R₁₀ and R₁₁ areindividually selected from the group consisting of H, aryl,heterocyclyl, alkyl, aralkyl and heterocyclylalkyl; R₁₂ is selected fromthe group consisting of NR₉, S, or O; R₁₃ is alkyl unsubstituted orsubstituted by a member selected from the group consisting of alkyl,—OR₁₀, —S(O)_(m)R₁₀ (m is 0, 1, or 2) and —N(R₁₀) (R₁₁) R₁₄ is H oralkyl; combined with at least one other anti-cancer agent selected fromthe group consisting of gemcitabine, taxol, taxol analogues andfarnesyltransferase inhibitor selected from the group consisting of: acompound of the formula

wherein n1 is 0 or 1; X, is independently, each time that it occurs,(CHR¹¹)_(n3) (CH₂)_(n4)Z (CH₂)_(n5); Z is selected from the groupconsisting of O, N(R¹²), S, and a bond; n3 is, independently, each timethat it occurs, 0 or 1; each of n4 and n5 are, independently, each timethat they occur, 0, 1, 2 or 3; Y is, independently, each time that itoccurs, selected from the group consisting of CO, CH₂, CS, and a bond;R¹ is selected from the group consisting of

and N(R²⁴R²⁵) each of R², R¹¹, and R¹² are individually, each time thatit occurs, selected from the group consisting of H, —(C₁₋₆)alkyl and anaryl unsubstituted or substituted by at least one member selected fromthe group consisting of R⁸ or R³⁰, each substituent being chosenindependently of the others; R³ is, independently, each time that itoccurs, selected from the group consisting of H, —(C₁₋₆)alkyl,—(C₂₋₆)alkenyl, —(C₂₋₆)alkynyl, —(C₃₋₆)cycloalkyl,—(C₃₋₆)cycloalkyl(C₁₋₆)alkyl, —(C₅₋₇)cycloalkenyl,—(C₅₋₇)cycloalkenyl(C₁₋₆)alkyl, aryl, aryl(C₁₋₆)alkyl, heterocyclyl, andheterocyclyl(C₁₋₆)alkyl unsubstituted or substituted by at least oneR³⁰, each substituent being chosen independently of the others; each ofR¹ and R⁵ are, independently, each time that it occurs, selected fromthe group consisting of H, —(C₁₋₆)alkyl, —(C₃₋₆)cycloalkyl, aryl andheterocyclyl unsubstituted or substituted by at least one R³⁰, eachsubstituent being chosen independently of the others, or R⁴ and R⁵ whentaken together with the carbon atoms to which they are attached togetherform aryl; R⁶ is, independently, each time that it occurs, selected fromthe group consisting of H, —(C₁₋₆)alkyl, —(C₂₋₆)alkenyl,—(C₃₋₆)cycloalkyl, —(C₃₋₆) cycloalkyl(C₁₋₆)alkyl, —(C₅₋₇) cycloalkenyl,—(C₅₋₇) cycloalkenyl(c₁₋₆)alkyl, aryl, aryl(C₁₋₆)alkyl, heterocyclyl andheterocyclyl(C₁₋₆)alkyl unsubstituted or substituted by at least onemember selected from the group consisting of —OH, —(C₁₋₆)alkyl,—(C₁₋₆)alkoxy, —N(R⁸R⁹), —COOH, —CON(R⁸R⁹) and halo, each substituentbeing chosen independently of the others; R⁷ is, independently, eachtime that it occurs, selected from the group consisting of H, ═O, ═S, H—(C₁₋₆)alkyl, —(C₂₋₆)alkenyl, —(C₃₋₆)cycloalkyl,—(C₃₋₆)cycloalkyl(C₁₋₆)alkyl, —(C₅₋₇) cycloalkenyl,—(C₅₋₇)cycloalkenyl(C₁₋₆)alkyl, aryl, aryl(C₁₋₆)alkyl, heterocyclyl andheterocyclyl(C₁₋₆)alkyl unsubstituted or substituted with at least onemember selected from the group consisting of —OH, —(C₁₋₆)alkyl,—(C₁₋₆)alkoxy, —N(R⁸R⁹), —COOH, —CON(R⁸R⁹) and halo, each substituentbeing chosen independently of the others; each of R⁸ and R⁹ are,independently, each time that it occurs, selected from the groupconsisting of H, (C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₂₋₆)alkynyl, aryl, andaryl(C₁₋₆)alkyl; R¹⁰ is C; or, when n1=0, R⁶ and R⁷ can be takentogether with the carbon atoms to which they are attached form aryl orcyclohexyl; R²¹ is, independently, each time that it occurs, selectedfrom the group consisting of (C₁₋₆)alkyl and aryl(C₁₋₆)alkylunsubstituted or substituted by at least one R⁸ or R³⁰, each substituentbeing chosen independently of the others; R²² is selected from the groupconsisting of H, (C₁₋₆)alkylthio, (C₃₋₆)cycloalkylthio, R⁸—CO—, and

each of R²⁴ and R²⁵ is independently, each time that it occurs, selectedfrom the group consisting of H, (C₁₋₆)alkyl and aryl (C₁₋₆) alkyl; R³⁰is, independently, each time that it occurs, selected from the groupconsisting of —(C₁₋₆)alkyl, —O—R⁸, —S(O)_(n6)R⁸, —S(O)_(n7)N(R⁸R⁹),—N(R⁸R⁹), —CN, —NO₂, —CO₂R⁸, —CON(R⁸R⁹), —NCO—R⁸, and halogen, each ofn6 and n7 is, independently, each time that it occurs, 0, 1 or 2; saidheterocyclyl is selected from the group consisting of azepinyl,benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl,benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl,benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl,dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothio-pyranylsulfone, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl,indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl,isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl,oxadiazolyl, 2-oxoazepinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxopyrrolidinyl, piperidyl, piperazinyl, pyridyl, pyridyl-N-oxide,quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolinyl,tetahydro-quinolinyl, thiamorpholinyl, thiamorpholinyl sulfoxide,thiazolyl, thiazolinyl, thienofuryl, thienothienyl and thienyl; saidaryl radical being phenyl or naphthyl; with the proviso that when n1=1,R¹⁰ is C and R⁶ is H, then R¹⁰ and R⁷ can, taken together, form

or when n1=1, R¹⁰ is C, and R⁷ is ═O, H, or ═S, then R¹⁰ and R⁶ can,taken together, form

with each of X¹, X², and X³ is independently selected from the groupconsisting of H, halogen, —NO₂, —NCO—R⁸, —CO₂R⁸, —CN, and —CON(R⁸R⁹);and when R¹ is N(R²⁴R²⁵), then n3 is 1, each of n4 and n5 is 0, Z is abond, and R³ and R¹¹ can, taken together, form

n2 is an integer from 1 to 6, and each of X⁴ and X⁵ is independentlyselected from the group consisting of H, —(C₁₋₆)alkyl and aryl, or X⁴and X⁵ taken together, form (C₃₋₆)cycloalkyl, a compound of the formula

wherein R¹ is selected from the group consisting of H, —OR¹⁰ and—NR¹¹R¹²; R² is H or alkyl; R³, R⁴ and R⁵ are independently selectedfrom the group consisting of H, halogen, alkyl, trihalomethyl, hydroxy,cyano and alkoxy; R⁶ is H or alkyl; R⁷ is selected from the groupconsisting of halogen, alkyl, hydroxyalkyl, amino, and hydroxycarbonyl;R⁸ and R⁹ are independently selected from the group consisting of H,halogen, cyano, alkyl, trihalomethyl, alkoxy, alkylthio anddialkylamino; R¹⁰ is selected from the group consisting of H, alkyl andalkylcarbonyl; R¹¹ is H or alkyl; R¹² is selected from the groupconsisting of H, alkyl and alkylcarbonyl; and Y is O or S; and of apharmaceutically acceptable salt of a compound of formula (II) or acompound of formula (III).
 5. A composition of claim 4, wherein thetransduction inhibitor of heterotrimeric G protein signals is a compoundof sub-formula (I_(A)) wherein: R₁ is H; R₂ and R₃ are independently Hor lower alkyl; R₄ is O; R₅ is selected from the group consisting of H,lower alkyl, cycloalkyl and cycloalkylalkyl; R₆ is aryl unsubstituted orsubstituted by a member selected from the group consisting of OH, alkyl,lower alkoxy, —N(R₁₀) (R₁₁), —COOH, —CON(R₁₀) (R₁₁) and halo; R₁₀ andR₁₁ are independently H or lower alkyl; and a pharmaceuticallyacceptable salt thereof.
 6. A composition of claim 4 wherein theanti-cancer agent combined with the transduction inhibitor ofheterotrimeric G protein signals is a compound of the formula

wherein R¹ is

R²¹ is aralkyl unsubstituted or substituted by at least one memberselected from the group consisting of halogen, cyano, hydroxy, alkoxy,amino, alkylamino and dialkylamino; R⁴ is aryl unsubstituted orsubstituted by at least one member of the group consisting of halogen,hydroxy, alkoxy, amino, alkylamino and dialkylamino; X is alkylene of 1to 6 carbon atoms; Y is CO; n1=1, R¹⁰ is C, R⁶ is H and R¹⁰ and R⁷ takentogether, form

each of X¹, X², and X³ is independently H or halogen and apharmaceutically acceptable salt thereof.
 7. The composition of claim 4wherein the anti-cancer agent combined with the transduction inhibitorof heterotrimeric G protein signals is a compound of the formula

wherein R¹ is OH or NH₂; R² is alkyl; one of R³, R⁴ and R⁵ is halogen;R⁶ is alkyl; one of R⁸ and R⁹ is halogen; Y is O; and a pharmaceuticallyacceptable salt thereof.
 8. A composition of claim 1 wherein theinhibitor of G proteins is selected from the group consisting of-7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-(2-methylphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;and-7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-phenyl-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;and pharmaceutically acceptable salts thereof.
 9. The composition ofclaim 1, wherein the anti-cancer agent is selected from the groupconsisting of1-(2-(1-((4-cyano)phenylmethyl)imidazol-4-yl)-1-oxoethyl-2,5-dihydro-4-(2-methoxyphenyl)imidazo[1,2c][1,4]benzodiazepine,4-(2-bromophenyl)-1-(2-(1-((4-cyano-3-methoxy)phenylmethyl)-imidazo-5-yl)-1-oxoethyl)-1,2-dihydro-8-fluoroimidazo[1,2a](1,4)-benzodiazepine;(±)-4-(3-chlorophenyl)-6-[(4-chloro-phenyl)-amino-(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)quinolinone,taxol and gemcitabine.
 10. The composition of claim 1 wherein anadditional anti-cancer compound, different from the anti-cancer agentcombined with the transduction inhibitor of heterotrimeric G proteinsignals, is selected from the group consisting of-1-(2-(1-((4-cyano)phenylmethyl)imidazol-4-yl)-1-oxoethyl-2,5-dihydro-4-(2-methoxyphenyl)imidazo[1,2c][1,4)benzodiazepine;-4-(2-bromophenyl)-1-(2-(1-((4-cyano-3-methoxy)phenylmethyl)-imidazo-5-yl-1-oxoethyl)-1,2-dihydro-8-fluoro-imidazo[1,2a](1,4]-benzodiazepine;-±-4-(3-chlorophenyl)-6-[(4-chlorophenyl)-amino-(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)quinolinone;taxol; gemcitabine; and a pharmaceutically acceptable salt thereof. 11.The composition of claim 7 wherein R² is methyl.
 12. A method oftreating cancer in warm-blooded animals comprising administering towarm-blooded animals in need thereof an antitumorally effective amountof a composition of claim
 1. 13. A method of treating cancer inwarm-blooded animals comprising administering to warm-blooded animals inneed thereof an antitumorally effective amount of a composition of claim4.
 14. A method of treating cancer in warm-blooded animals comprisingadministering to warm-blooded animals in need thereof an antitumorallyeffective amount of a composition of claim 10.